A fresh look at the causes and treatments of recurrent miscarriage, especially its immunological aspects

The scientific basis for many traditionally accepted causes of recurrent miscarriage (RM) is weak. A significant proportion of RM cases with relatively few miscarriages can presumably be attributed to the random occurrence of consecutive chromosomally abnormal conceptions. New insights in the immunological interactions taking place at the feto-maternal interface provide us with the opportunity to propose detailed pathophysiological models for immunologically mediated RM. Scientific support for the theory that RM is a consequence of graft rejection-like alloimmune reactions against paternal human leukocyte antigens on the fetus is sparse. Conversely, there is considerable evidence that decidual natural killer cells play a role in the implantation and early invasion of the trophoblast and in the pathogenesis of RM. T helper (Th) cells from women with RM react against trophoblast antigens in vitro with the secretion of mainly interleukin-2 and interferon-gamma (a so-called Th1 response), which are known to inhibit trophoblast growth. The predisposition to a Th1 response against a given antigen may be determined by an individual's class II histocompatibility genes. In accordance with this, case-control, prospective and family studies indicate that maternal histocompatibility haplotypes comprising DR1 and DR3 alleles confer susceptibility to RM. The frequent occurrence of autoantibodies in women with RM is compatible with the theory of a Th1 response against trophoblast as a cause of the syndrome, but the autoantibodies themselves probably do not cause RM.